Staphylococcus aureus is a gram positive bacteria that possesses a multitude of virulence factors. It is a frequent and severe pathogen in hospitals and of increasing concern in the community, where it results in severe skin infections, pneumonia, sepsis and lethal bacterial endocarditis. A significant proportion of these infections are the result of methicillin-resistant S. aureus (MRSA). We have developed a highly immunogenic prototype nanoparticle vaccine capable of rapidly eliciting antibody against the pore neutralizing determinant (PND) within alpha toxin (AT), a ubiquitous and critical virulence factor of MRSA. Previous work has demonstrated that Ab against the PND is highly efficacious in preventing tissue injury and bacterial growth in a rigorous mouse dermonecrosis model, and in protecting mice in a lethal model of S. aureus pneumonia. In this project, we will utilize the human hepatitis core antigen platform to develop nanoparticle vaccines capable of neutralizing the key leukotoxins including gamma toxin, Panton Valentine leukocidin, LukED and LukGH, which are critical, secreted virulence factors which enable S. aureus to evade host immunity, and a nanoparticle vaccine targeting the previously validated PND of AT. The vaccines emerging from these studies will be uniquely effective against MRSA infections and will ideally be the basis of an efficacious, multivalent nanoparticle vaccine for MRSA.